CMTR2 (cap methyltransferase 2) is an S-adenosyl-L-methionine-dependent methyltransferase that catalyzes 2'-O-ribose methylation of the second nucleotide in mRNA 5' cap structures, converting cap0 to cap2 and preferentially modifying cap1 substrates 1. The enzyme functions in both nucleus and cytoplasm 1, with structural analysis revealing a distinct RNA recognition mechanism that differs significantly from viral methyltransferases 2. CMTR2 exhibits cooperative activities with other capping methyltransferases (RNMT and CMTR1) rather than purely sequential functions 3. Loss of Cmtr2 in mice causes embryonic lethality with transcript misregulation independent of interferon pathway activation, indicating essential roles beyond innate immune evasion 4. Clinically, rare inactivating CMTR2 variants associate with increased susceptibility to lung adenocarcinoma and cutaneous melanoma 5. In lung cancer, CMTR2 mutations (occurring in ~3.8% of cases) disrupt alternative splicing patterns, creating a distinct molecular subtype with therapeutic vulnerabilities 6. CMTR2-deficient tumors demonstrate increased sensitivity to RNA splicing modulators and immune checkpoint blockade therapy, with retrospective patient data confirming enhanced immunotherapy response 6.